Gender affirming hormone therapy preserves skeletal maturation in young mice via the gut microbiome.

Gender affirming hormone therapy (GAHT) is often prescribed to transgender (TG) adolescents to alleviate gender dysphoria, but the impact of GAHT on the growing skeleton is unclear. We found GAHT to improve trabecular bone structure via increased bone formation in young male mice and not to affect trabecular structure in female mice. GAHT modified gut microbiome composition in both male and female mice. However, fecal microbiota transfers (FMT) revealed that GAHT-shaped gut microbiome was a communicable regulator of bone structure and turnover in male, but not in female mice. Mediation analysis identified two species of Bacteroides as significant contributors to the skeletal effects of GAHT in male mice, with Bacteroides supplementation phenocopying the effects of GAHT on bone. Bacteroides have the capacity to expand Treg populations in the gut. Accordingly, GAHT expanded intestinal regulatory T cells (Tregs) and stimulated their homing to the bone marrow (BM) in male but not in female mice. Attesting to the functional relevance of Tregs, pharmacological blockade of Treg expansion prevented GAHT-induced bone anabolism. In summary, in male mice GAHT stimulated bone formation and improved trabecular structure by promoting Treg expansion via a microbiome-mediated effect. In female mice GAHT neither improved nor impaired trabecular structure.

The impact of MYD88 and PIM1 in mature large B-cell non-Hodgkin lymphomas: Defining element of their evolution and prognosis.

Sequence studies of the entire exome and transcriptome of lymphoma tissues have identified MYD88 and PIM1 as involved in the development and oncogenic signaling. We aimed to determine the frequency of MYD88 and PIM1 mutations, as well as their expressions in conjunction with the clinicopathological parameters identified in mature large B-cell non-Hodgkin lymphomas. The ten-year retrospective study included 50 cases of mature large B-cell lymphoma, diagnosed at the Pathology Department of the Emergency County Hospital of Constanta and Sacele County Hospital of Brasov. They were statistically analyzed by demographic, clinicopathological, and morphogenetic characteristics. We used a real-time polymerase chain reaction technique to identify PIM1 and MYD88 mutations as well as an immunohistochemical technique to evaluate the expressions of the 2 genes. Patients with lymphoma in the small bowel, spleen, brain, and testis had a low-performance status Eastern Cooperative Oncology Group (P = .001). The Eastern Cooperative Oncology Group performance status represented an independent risk factor predicting mortality (HR = 9.372, P < .001). An increased lactate dehydrogenase value was associated with a low survival (P = .002). The international prognostic index score represents a negative risk factor in terms of patient survival (HR = 4.654, P < .001). In cases of diffuse large B-cell lymphoma (DLBCL), immunopositivity of MYD88 is associated with non-germinal center B-cell origin (P < .001). The multivariate analysis observed the association between high lactate dehydrogenase value and the immunohistochemical expression of PIM1 or with the mutant status of the PIM1 gene representing negative prognostic factors (HR = 2.066, P = .042, respectively HR = 3.100, P = .004). In conclusion, our preliminary data suggest that the oncogenic mutations of PIM1 and MYD88 in our DLBCL cohort may improve the diagnosis and prognosis of DLBCL patients in an advanced stage.

The Impact of Vitamin D Deficiency on Infants' Health.

Vitamin D is an essential nutrient that plays a vital role in bone health and musculoskeletal development. The aim of this narrative review is to present up-to-date information about the impact of vitamin D deficiency (VDD) on the health status of infants in their first year of life. Vitamin D is indispensable for skeletal growth and bone health, and emerging research suggests that it may also have significant roles in maternal and fetal health. VDD affects a large proportion of infants according to current guidelines. However, its prevalence varies depending on geographic location, skin pigmentation, and the time of year. Based on current guidelines for normal vitamin D levels and recommended daily intake, studies suggest that VDD is a global health issue with potentially significant implications for those at risk, especially infants. Our understanding of the role of vitamin D has improved significantly in the last few decades. Systematic reviews and meta-analyses investigating the effect of vitamin D on preterm birth, low birth weight, anthropometric parameters, and health outcomes such as infectious diseases in infants, have found conflicting or inconsistent results. It is important to encourage further research to fill in these knowledge gaps and develop national or global strategies that ease the burden of VDD, especially in groups at risk.

Comparison of Ki67 Proliferation Index in Gastrointestinal Non-Hodgkin Large B-Cell Lymphomas: The Conventional Method of Evaluation or AI Evaluation?

The most common NHL subtype in SEEU is DLBCL (39%), and it manifests with a variety of cellular morphologies and a high proliferation index. Also, the GI tract is the most common site of extranodal NHLs, and most NHLs involving the GI tract are of B-cell lineage, of which diffuse large B-cell lymphoma is the most common subtype, irrespective of location. The last few years have seen digital pathology as a vital technology that has a positive impact on diagnostics, but studies on the use of DP for lymphoma identification, however, are still restricted to only determining whether a tumor is present or absent. Using the example of cases of malignant NHL, we aim to investigate the diagnostic utility of DP using QuPath software in evaluating the proliferation index and the prognostic significance and to show that improved visualization and analysis contribute to the convergence of these complementary diagnostic modalities for lymphomas. The average proliferation index (Ki67) was 58.33% with values between 10% and 85%. After the stratification of the cases, an increased proliferation index was observed in the majority of cases (53.33%), and this aspect was associated with the advanced age of the patients (p = 0.045). Visual assessment provides lower Ki67 values than automated digital image analysis. However, the agreement coefficient between the conventional method and the AI method indicates an excellent level of reliability (ICC1-0.970, ICC2-0.990). The multivariate analysis revealed that in the cases where the proliferation index Ki67 is high (˃70%), the IPI score represents an important risk factor predicting mortality (HR = 10.597, p = 0.033).

Callus γδ T cells and microbe-induced intestinal Th17 cells improve fracture healing in mice.

IL-17A (IL-17), a driver of the inflammatory phase of fracture repair, is produced locally by several cell lineages including γδ T cells and Th17 cells. However, the origin of these T cells and their relevance for fracture repair are unknown. Here, we show that fractures rapidly expanded callus γδ T cells, which led to increased gut permeability by promoting systemic inflammation. When the microbiota contained the Th17 cell-inducing taxon segmented filamentous bacteria (SFB), activation of γδ T cells was followed by expansion of intestinal Th17 cells, their migration to the callus, and improved fracture repair. Mechanistically, fractures increased the S1P receptor 1-mediated (S1PR1-mediated) egress of Th17 cells from the intestine and enhanced their homing to the callus through a CCL20-mediated mechanism. Fracture repair was impaired by deletion of γδ T cells, depletion of the microbiome by antibiotics (Abx), blockade of Th17 cell egress from the gut, or Ab neutralization of Th17 cell influx into the callus. These findings demonstrate the relevance of the microbiome and T cell trafficking for fracture repair. Modifications of microbiome composition via Th17 cell-inducing bacteriotherapy and avoidance of broad-spectrum Abx may represent novel therapeutic strategies to optimize fracture healing.

Diffuse large B cell lymphoma CD5-positive arising in an immune deficiency and immune dysregulation setting: A case report and brief review of the literature.

RATIONALE: In the era of antiretroviral therapy, lymphoma is the primary cause of cancer-related death among human immunodeficiency virus (HIV)-infected people and the most prevalent and aggressive non-Hodgkin lymphoma is diffuse large B cell lymphoma, which usually has an aggressive clinical course. CD5-positive diffuse large B cell lymphoma (DLBCL) is an insufficiently studied, relatively new entity, which accounts for 5% to 10% of the DLBCL population. The current study presents the clinicopathological features, diagnostic approach, and clinical outcomes of this HIV-related lymphoma and highlights the importance of the early diagnosis of CD5-positive DLBCL. PATIENT CONCERNS: We present a case of a 30-year-old male patient, with a medical history of HIV-positive serology and antiviral treatment, presenting with diffuse abdominal pain and symptoms related to obstruction or perforation, followed by exploratory laparotomy and surgical resection of the small intestine with other areas of involvement. The surgical specimen was morphologically evaluated and immunohistochemical stained. DIAGNOSES AND INTERVENTIONS: Histopathologic examination revealed a diffuse neoplastic proliferation of large B lymphocytes within the small intestine, lacking features of other defined types of large B cell lymphoma. The diagnosis of CD5-positive DLBCL subtype was made after immunostaining with twelve monoclonal antibodies (CD3, CD5, CD10, CD20, CD23, CD30, CD68, Cyclin D1, MUM1, Bcl2, Bcl6, and Ki-67). The expression profile of immunohistochemical markers (CD10, Bcl6, and MUM1) established the cell of origin of this case of DLBCL by using the Hans algorithm. LESSONS: The current report highlights the importance of early diagnosis of CD5-positive DLBCL because of its poor prognosis and calls attention to the critical importance to identify immunodeficiencies because doing so affects the types of treatments available. Although cell-of-origin is useful for predicting outcomes, the germinal center B cell like and activated-B cell like subtypes remain heterogeneous, with better, and worse prognostic subsets within each group.

Changes in Platelet Function in Preterm Newborns with Prematurity Related Morbidities.

Platelet indices represent useful biomarkers to express the thromboembolic status, inflammatory response, and oxidative stress in preterm newborns. Our study presented platelet count and function changes in prematurity-related morbidities such as respiratory distress syndrome, intraventricular bleeding, and anemia of prematurity in preterm newborn cases reported to healthy full-term newborns by flow cytometry and hematological methods. The platelet volume represents the average size of platelets in the blood samples, showing the significantly increased values in preterm newborns compared with healthy full-term newborns due to increasing activated platelet production. Flow cytometric analysis of immature platelet fractions (IPF) made using thiazole orange staining to detect their mRNA content and a glycoprotein (anti-GPIIIa) antibody for platelet gating. CD61-TO expression from premature newborns was significantly lower compared to healthy full-term neonates. Preterm newborn cases with respiratory distress syndrome and a need for respiratory support (RDS+) were characterized by a significantly increased platelet volume and a decreased immature platelet fraction reported in RDS- cases. Evaluating the platelet function in the newborn is difficult because the laboratory methodologies work with small quantities of newborn blood samples. The immature platelet fractions and platelet volume promise to be diagnostic biomarkers for diseases.

The microbiome restrains melanoma bone growth by promoting intestinal NK and Th1 cell homing to bone.

Bone metastases are frequent complications of malignant melanoma leading to reduced quality of life and significant morbidity. Regulation of immune cells by the gut microbiome influences cancer progression, but the role of the microbiome in tumor growth in bone is unknown. Using intracardiac or intratibial injections of B16-F10 melanoma cells into mice, we showed that gut microbiome depletion by broad-spectrum antibiotics accelerated intraosseous tumor growth and osteolysis. Microbiome depletion blunted melanoma-induced expansion of intestinal NK cells and Th1 cells and their migration from the gut to tumor-bearing bones. Demonstrating the functional relevance of immune cell trafficking from the gut to the bone marrow (BM) in bone metastasis, blockade of S1P-mediated intestinal egress of NK and Th1 cells, or inhibition of their CXCR3/CXCL9-mediated influx into the BM, prevented the expansion of BM NK and Th1 cells and accelerated tumor growth and osteolysis. Using a mouse model, this study revealed mechanisms of microbiota-mediated gut-bone crosstalk that are relevant to the immunological restraint of melanoma metastasis and tumor growth in bone. Microbiome modifications induced by antibiotics might have negative clinical consequences in patients with melanoma.

Photoferrotrophy and phototrophic extracellular electron uptake is common in the marine anoxygenic phototroph Rhodovulum sulfidophilum.

Photoferrotrophy allows anoxygenic phototrophs to use reduced iron as an electron donor for primary productivity. Recent work shows that freshwater photoferrotrophs can use electrons from solid-phase conductive substances via phototrophic extracellular electron uptake (pEEU), and the two processes share the underlying electron uptake mechanism. However, the ability of marine phototrophs to perform photoferrotrophy and pEEU, and the contribution of these processes to primary productivity is largely unknown. To fill this knowledge gap, we isolated 15 new strains of the marine anoxygenic phototroph Rhodovulum sulfidophilum on electron donors such as acetate and thiosulfate. We observed that all of the R. sulfidophilum strains isolated can perform photoferrotrophy. We chose strain AB26 as a representative strain to study further, and find that it can also perform pEEU from poised electrodes. We show that during pEEU, AB26 transfers electrons to the photosynthetic electron transport chain. Furthermore, systems biology-guided mutant analysis shows that R. sulfidophilum AB26 uses a previously unknown diheme cytochrome c protein, which we call EeuP, for pEEU but not photoferrotrophy. Homologs of EeuP occur in a range of widely distributed marine microbes. Overall, these results suggest that photoferrotrophy and pEEU contribute to the biogeochemical cycling of iron and carbon in marine ecosystems.