Safety and efficacy of G-CSF after allogeneic hematopoietic cell transplantation using post-transplant cyclophosphamide: clinical and in vitro examination of endothelial activation.

Since 2021 the use of G-CSF was implemented in allo-HCT with PTCY-based prophylaxis with the aim of shortening the aplastic phase and reducing infectious complications. This study investigates the effectiveness of this change in protocol performed at our institution. One-hundred forty-six adults undergoing allo-HCT with PTCY-based prophylaxis were included, and among them, 58 (40%) received G-CSF. The median of days to neutrophil engraftment was shorter in the G-CSF group (15 vs. 20 days, p < 0.001). Patients receiving G-CSF had a lower incidence of day +30 bacterial bloodstream infections (BSI) than the rest (20.7% vs. 47.7%, p < 0.001). GVHD, SOS, and TA-TMA incidences were comparable between groups, and using G-CSF did not impact on survival. Endothelial activation was investigated using EASIX and by the measurement of soluble biomarkers in cryopreserved plasma samples obtained on days 0, +7, +14 and +21 of 39 consecutive patients (10 received G-CSF) included in the study. EASIX, VWF:Ag, sVCAM-1, sTNFRI, ST2, REG3α, TM and NETs medians values were comparable in patients receiving G-CSF and those who did not. Compared with allo-HCT performed without G-CSF, the addition of G-CSF to PTCY-based allo-HCT accelerated neutrophil engraftment contributing on decreasing BSI incidence, and without inducing additional endothelial activation.

Advanced materials for micro/nanorobotics.

Autonomous micro/nanorobots capable of performing programmed missions are at the forefront of next-generation micromachinery. These small robotic systems are predominantly constructed using functional components sourced from micro- and nanoscale materials; therefore, combining them with various advanced materials represents a pivotal direction toward achieving a higher level of intelligence and multifunctionality. This review provides a comprehensive overview of advanced materials for innovative micro/nanorobotics, focusing on the five families of materials that have witnessed the most rapid advancements over the last decade: two-dimensional materials, metal-organic frameworks, semiconductors, polymers, and biological cells. Their unique physicochemical, mechanical, optical, and biological properties have been integrated into micro/nanorobots to achieve greater maneuverability, programmability, intelligence, and multifunctionality in collective behaviors. The design and fabrication methods for hybrid robotic systems are discussed based on the material categories. In addition, their promising potential for powering motion and/or (multi-)functionality is described and the fundamental principles underlying them are explained. Finally, their extensive use in a variety of applications, including environmental remediation, (bio)sensing, therapeutics, etc., and remaining challenges and perspectives for future research are discussed.

Efficacy of escalating therapy with brentuximab vedotin-AVD in advanced stage Hodgkin lymphoma patients with positive interim positron emission tomography after ABVD.

Patients with advanced-stage Hodgkin lymphoma treated with ABVD who have a positive interim FDG-PET (iPET) have a poor prognosis. Escalation to BEACOPP has been shown to improve progression-free survival (PFS). However, randomized trials are lacking to determine the best strategy for intensification. We report on A-AVD escalation treatment outcomes for 15 iPET-positive patients post-ABVD. Overall response and complete response rates were 80% and 60%, respectively. Four patients underwent salvage therapy followed by autologous stem cell transplantation. At a median 17-month follow-up, all patients are alive, 87% in complete remission, and 1-year PFS was 57.8%. For patients ineligible for BEACOPP due to age, comorbidities, or preference, A-AVD escalation may be a viable alternative.

Defective thyroid hormone transport to the brain leads to astroglial alterations.

Allan-Herndon-Dudley syndrome (AHDS) is a rare X-linked disorder that causes severe neurological damage, for which there is no effective treatment. AHDS is due to inactivating mutations in the thyroid hormone transporter MCT8 that impair the entry of thyroid hormones into the brain, resulting in cerebral hypothyroidism. However, the pathophysiology of AHDS is still not fully understood and this is essential to develop therapeutic strategies. Based on evidence suggesting that thyroid hormone deficit leads to alterations in astroglial cells, including gliosis, in this work, we have evaluated astroglial impairments in MCT8 deficiency by means of magnetic resonance imaging, histological, ultrastructural, and immunohistochemical techniques, and by mining available RNA sequencing outputs. Apparent diffusion coefficient (ADC) imaging values obtained from magnetic resonance imaging showed changes indicative of alterations in brain cytoarchitecture in MCT8-deficient patients (n = 11) compared to control subjects (n = 11). Astroglial alterations were confirmed by immunohistochemistry against astroglial markers in autopsy brain samples of an 11-year-old and a 30th gestational week MCT8-deficient subjects in comparison to brain samples from control subjects at similar ages. These findings were validated and further explored in a mouse model of AHDS. Our findings confirm changes in all the astroglial populations of the cerebral cortex in MCT8 deficiency that impact astrocytic metabolic and mitochondrial cellular respiration functions. These impairments arise early in brain development and persist at adult stages, revealing an abnormal distribution, density, morphology of cortical astrocytes, along with altered transcriptome, compatible with an astrogliosis-like phenotype at adult stages. We conclude that astrocytes are potential novel therapeutic targets in AHDS, and we propose ADC imaging as a tool to monitor the progression of neurological impairments and potential effects of treatments in MCT8 deficiency.

Outcomes of older adults undergoing allogeneic hematopoietic cell transplantation with post-transplant cyclophosphamide based prophylaxis.

This study evaluates the feasibility of using post-transplant cyclophosphamide (PTCY) prophylaxis in allo-hematopoietic cell transplantation (HCT) for adults aged 65 and older. PTCY is increasingly used to prevent graft-versus-host disease (GVHD) across all donor types, but concerns remain about potential risks, especially in older patients. Fifty-seven adults aged 65 or older with hematological malignancies, undergoing their first allo-HCT with PTCY prophylaxis between January 2011 and January 2023 were included. Overall, 94.8% of patients achieved primary engraftment. The median durations for neutrophil and platelet engraftments were 19 and 21 days. The day +30 cumulative incidence of bacterial bloodstream infection was 43.9%. No CMV reactivations occurred within the first 100 days after letermovir implementation. The day +180 cumulative incidences of grade II-IV and III-IV acute GVHD, and the 2-year cumulative incidence of moderate/severe chronic GVHD were 26.3%, 10.5%, and 4.8%. Eighteen patients (31.6%) relapsed, and 30 (52.6%) died, with relapse (16.4%) and infection (11.5%) being the main causes of death. The estimated 2-year overall survival, non-relapse mortality, cumulative incidence of relapse, and GVHD-free relapse-free survival rates were 45.5%, 27.1%, 33.9%, and 37.0%. Adults aged 70 or older had similar outcomes to those aged 65-69. This study confirms the safety and feasibility of PTCY-based allo-HCT in older adults.

Marked increase in cryptosporidiosis cases, Spain, 2023.

BackgroundBy mid-September 2023, several event notifications related to cryptosporidiosis had been identified from different regions in Spain. Therefore, a request for urgent notification of cryptosporidiosis cases to the National Surveillance Network was launched.AimWe aimed at assessing the extent of the increase in cases, the epidemiological characteristics and the transmission modes and compared to previous years.MethodsWe analysed data on case notifications, outbreak reports and genotypes focusing on June-October 2023 and compared the results to 2016-2022.ResultsIn 2023, 4,061 cryptosporidiosis cases were notified in Spain, which is an increase compared to 2016-2022. The cumulative incidence was 8.3 cases per 100,000 inhabitants in 2023, sixfold higher than the median of 1.4 cases per 100,000 inhabitants 2016-2022. Almost 80% of the cases were notified between June and October. The largest outbreaks were related to contaminated drinking water or swimming pools. Cryptosporidium hominis was the most common species in the characterised samples (115/122), and the C. hominis IfA12G1R5 subtype, previously unusual in Spain, was detected from 76 (62.3%) of the 122 characterised samples.ConclusionsA substantial increase in cryptosporidiosis cases was observed in 2023. Strengthening surveillance of Cryptosporidium is essential for prevention of cases, to better understand trends and subtypes circulating and the impact of adverse meteorological events.

Longitudinal lung function trajectories in response to azithromycin therapy for chronic lung disease in children with HIV infection: a secondary analysis of the BREATHE trial.

BACKGROUND: Chronic lung disease (CLD) is common among children with HIV (CWH) including in those taking antiretroviral therapy (ART). Azithromycin has both antimicrobial and anti-inflammatory effects and has been effective in improving lung function in a variety of lung diseases. We investigated lung function trajectories among CWH with CLD on ART enrolled in a randomized controlled trial of adjuvant azithromycin. We also investigated factors that modified the effect of azithromycin on lung function. METHODS: The study used data from a double-blinded placebo-controlled trial conducted in Malawi and Zimbabwe of 48 weeks on azithromycin (BREATHE: ClinicalTrials.gov NCT02426112) among CWH aged 6 to 19 years taking ART for at least six months who had a forced expiratory volume in one second (FEV1) z-score <-1.0. Participants had a further follow-up period of 24 weeks after intervention cessation. FEV1, forced vital capacity (FVC) and FEV1/FVC were measured at baseline, 24, 48 and 72-weeks and z-scores values calculated. Generalized estimating equations (GEE) models were used to determine the mean effect of azithromycin on lung-function z-scores at each follow-up time point. RESULTS: Overall, 347 adolescents (51% male, median age 15 years) were randomized to azithromycin or placebo. The median duration on ART was 6.2 (interquartile range: 3.8-8.6) years and 56.2% had an HIV viral load < 1000copies/ml at baseline. At baseline, the mean FEV1 z-score was - 2.0 (0.7) with 44.7% (n = 155) having an FEV1 z-score <-2, and 10.1% had microbiological evidence of azithromycin resistance. In both trial arms, FEV1 and FVC z-scores improved by 24 weeks but appeared to decline thereafter. The adjusted overall mean difference in FEV1 z-score between the azithromycin and placebo arms was 0.004 [-0.08, 0.09] suggesting no azithromycin effect and this was similar for other lung function parameters. There was no evidence of interaction between azithromycin effect and baseline age, lung function, azithromycin resistance or HIV viral load. CONCLUSION: There was no observed azithromycin effect on lung function z-scores at any time point suggesting no therapeutic effect on lung function. TRIAL REGISTRATION: ClinicalTrials.gov NCT02426112. First registered on 24/04/2015.

Reduced Dose of Post-Transplant Cyclophosphamide with Tacrolimus for the Prevention of Graft-versus-Host Disease in HLA-Matched Donor Peripheral Blood Stem Cell Transplants: A Prospective Pilot Study.

PTCY 50 mg/kg/day on days +3/+4 is an excellent strategy to prevent GVHD. However, its use is associated with adverse outcomes such as delayed engraftment, increased risk of infection, and cardiac complications. This pilot study evaluates the efficacy and toxicity of a reduced dose of PTCY (40 mg/kg/day) combined with tacrolimus in 22 peripheral blood HLA-matched alloHSCT patients. At day +100, the cumulative incidences of grade II-IV and III-IV acute GVHD were 18.2% and 4.5%, respectively. No grade IV acute GVHD or steroid-refractory disease was observed. The cumulative incidences of all-grade and moderate-severe chronic GVHD at 1-year were 11.4% and 6.4%, respectively. No patient died from transplant-related complications. Two-year OS and RFS were 77.1% and 58.3%, respectively. All patients engrafted, with neutrophil and platelet recovery occurring at a median of 15 (IQR 14-16) and 16 days (IQR 12-23), respectively. The cumulative incidences of bloodstream bacterial infections, polyomavirus BK hemorrhagic cystitis, HHV6 reactivation, CMV reactivation, and fungal infections were 13.6%, 9.1%, 9.1%, 4.6%, and 6%, respectively. Only one early cardiac event was observed. These results suggest that PTCY 40 mg/kg/day on a +3/+4 schedule provides adequate immunosuppression to allow for engraftment and prevent clinically significant GVHD with a low toxicity profile.

Improved Characterization of Soil Organic Matter by Integrating FT-ICR MS, Liquid Chromatography Tandem Mass Spectrometry, and Molecular Networking: A Case Study of Root Litter Decay under Drought Conditions.

Understanding of how soil organic matter (SOM) chemistry is altered in a changing climate has advanced considerably; however, most SOM components remain unidentified, impeding the ability to characterize a major fraction of organic matter and predict what types of molecules, and from which sources, will persist in soil. We present a novel approach to better characterize SOM extracts by integrating information from three types of analyses, and we deploy this method to characterize decaying root-detritus soil microcosms subjected to either drought or normal conditions. To observe broad differences in composition, we employed direct infusion Fourier-transform ion cyclotron resonance mass spectrometry (DI-FT-ICR MS). We complemented this with liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify components by library matching. Since libraries contain only a small fraction of SOM components, we also used fragment spectral cosine similarity scores to relate unknowns and library matches through molecular networks. This integrated approach allowed us to corroborate DI-FT-ICR MS molecular formulas using library matches, which included fungal metabolites and related polyphenolic compounds. We also inferred structures of unknowns from molecular networks and improved LC-MS/MS annotation rates from ∼5 to 35% by considering DI-FT-ICR MS molecular formula assignments. Under drought conditions, we found greater relative amounts of lignin-like vs condensed aromatic polyphenol formulas and lower average nominal oxidation state of carbon, suggesting reduced decomposition of SOM and/or microbes under stress. Our integrated approach provides a framework for enhanced annotation of SOM components that is more comprehensive than performing individual data analyses in parallel.

Current Microbiological Testing Approaches and Documented Infections at Febrile Neutropenia Onset in Patients with Hematological Malignancies.

INTRODUCTION: Identifying infection etiology in febrile neutropenia (FN) is vital. This study explores different microbiological approaches and their impact on diagnosing infections in patients with hematologic malignancies and FN. METHODS: Retrospective analysis conducted at Hospital Clinic of Barcelona details microbiological testing strategies used to diagnose infections at FN onset between January 2020 and July 2022. RESULTS: 4520 microbiological tests were ordered in 462 FN episodes, achieving a 10% test positivity rate with 200 (43.3%) episodes showing microbiological documentation of infection. Blood cultures (40.4%), non-culture blood tests (21.2%), respiratory tract samples (16.2%), were the most requested. Blood cultures exhibited the highest (16.9%) test positivity rates while non-culture blood tests showed the lowest (3.3%). Bacterial infections were present in 149/462 (32.3%) FN episodes. Viral infections (66/462, 14.3%)-notably respiratory viruses-were also frequent. Mortality rate at 60 days was 9.1%; documented infections were associated with a higher risk (15%). CONCLUSIONS: In the current landscape of antimicrobial diagnostics, our findings revealed the highest reported rate of microbiologically documented infections at FN onset. Bacterial infections are common; however, our data reiterates the significance of viral infections in causing fever. Optimizing FN management during respiratory viral infections remains a challenge for antimicrobial de-escalation. The low positivity rates observed in certain diagnostic tests emphasize the need for cost-effective diagnostic stewardship.

Tuning the electronic properties of Zr UiO-66 through defect-functionalised multivariate modulation.

The multivariate modulation of Metal-Organic Frameworks is presented as a valuable tool to introduce multiple functional units into UiO-66 while increasing its porosity. This manuscript encloses a comprehensive study using p-functionalised benzoate -NO2, -SO3 and -SH modulators, rationalizing the defects introduced and their impact on properties.

Isolation, Expansion, and Nucleofection of Neural Stem Cells from Adult Murine Subventricular Zone.

Isolation and expansion of neural stem cells (NSCs) from the subventricular zone (SVZ) of the adult mouse brain can be achieved in a medium supplemented with basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) as mitogens, producing clonal aggregates known as neurospheres. This in vitro system is a valuable tool for studying NSC potential. Transfection of siRNAs or genes carried in plasmids can be used to induce perturbations to gene expression and study NSC biology. However, the exogenous nucleic acid delivery to NSC cultures is challenging due to the low efficiency of central nervous system (CNS) cells transfection. Here, we present an improved nucleofection system that achieves high efficiency of gene delivery in expanded NSCs from adult murine SVZ. We demonstrate that this relatively simple method enhances gene perturbation in adult NSCs, surpassing traditional transfection protocols with survival rates exceeding 80%. Moreover, this method can also be applied in primary isolated NSCs, providing a crucial advancement in gene function studies through gene expression manipulation via knockdown or overexpression in neurosphere cultures.

Role of extracorporeal photopheresis in the management of acute and chronic graft versus disease: current status.

Extracorporeal photopheresis (ECP) is a therapy that combines the collection of mononuclear cells by apheresis, the addition of a photosensitizer (8-methoxisoralen), the illumination of the product with ultraviolet A light, and the immediate infusion of the product to the patient. Initially developed and approved to treat T-cell cutaneous lymphomas, soon started to be used to treat graft versus host disease (GvHD) developed after allogeneic hematopoietic-cell transplantation. The high response rate of ECP in skin, ocular, oral, pulmonary, and liver forms of chronic GvHD, the steroid-sparing effect, and the improved overall survival of treated patients, made ECP one of the second-line treatments used to treat steroid-resistant acute and chronic GVHD. Recently, the development of new drugs for treating GVHD has changed the position of ECP in the therapy of GVHD and has started to be used in combination with drugs for increasing the response rate to the treatment in severe or resistant forms of acute and chronic GVHD. ECP remains an essential therapeutic resource in the management of patients with refractory acute and chronic GVHD.

Management of deceased and living kidney donor with lithiasis: a multicenter retrospective study on behalf of the renal transplant group of the Spanish urological association.

BACKGROUND: To maximize the availability of suitable grafts and ensure effective management, several reports have demonstrated successful outcomes when using kidney grafts with urolithiasis. This multicenter study reports on the management and long-term outcomes of kidney transplantation using renal grafts with lithiasis. METHODS: Retrospective data from three Spanish hospitals were analyzed for kidney transplants involving grafts with nephrolithiasis performed between December 2009 and August 2023. The study included adult patients, excluding those with incomplete records. It evaluated stone characteristics, complications, and outcomes in recipients and in living kidney donors. RESULTS: Out of 38 analyzed kidney transplants, 57.9% were cadaveric and 42.1% were from living kidney donors. Most diagnoses were incidental during donor evaluation, with an average stone size of 7.06 mm. After follow-up (median 26 months), all recipients but one had functioning grafts, and there were no stone recurrences in both recipients and living kidney donors. Conservative management was adopted in 28 cases, while 10 cases required ex-vivo flexible ureterorenoscopy for stone removal. Following conservative management, 5 patients needed additional treatments for stone-related events. CONCLUSIONS: Kidneys with lithiasis can be considered for transplantation in selected cases, resulting in good functional outcomes with no stone recurrence in recipients or living donors.

Cyclophosphamide-free mobilisation increases safety while preserving the efficacy of autologous haematopoietic stem cell transplantation in refractory Crohn's disease patients.

BACKGROUND AND AIM: Autologous haematopoietic stem cell transplantation [AHSCT] is a therapeutic option for refractory Crohn's disease [CD]. However, high adverse event rates related to chemotherapy toxicity and immunosuppression limit its applicability. This study aims to evaluate AHSCT's safety and efficacy using a cyclophosphamide (Cy)-free mobilisation regimen. METHODS: A prospective observational study included 14 refractory CD patients undergoing AHSCT between June 2017 and October 2022. The protocol involved outpatient mobilisation with G-CSF 12-16 µg/kg/daily for 5 days, and optional Plerixafor 240 µg/d (1-2 doses) if the CD34+ cell count target was unmet. Standard conditioning with Cy and anti-thymocyte globulin was administered. Clinical, endoscopic, and radiological assessments were conducted at baseline and during follow-up. RESULTS: All patients achieved successful outpatient mobilisation (7 patients needed Plerixafor) and underwent transplantation. Median follow-up was 106 weeks (IQR 52-348). No mobilisation-related serious adverse events (SAEs) or CD worsening occurred. Clinical and endoscopic remission rates were 71% and 41.7% at 26 weeks, 64% and 25% at 52 weeks, and 71% and 16.7% at the last follow-up. The percentage of patients who restarted CD therapy for clinical relapse and/or endoscopic/radiological activity was 14% at 26 weeks, 57% at 52 weeks, and 86% at the last follow-up. Peripheral blood cell populations and antibody levels post-AHSCT were comparable to Cy-based mobilisation. CONCLUSIONS: Cy-free mobilisation is safe and feasible in refractory CD patients undergoing AHSCT. Although relapse occurs in a significant proportion of patients, clinical and endoscopic responses are achieved upon CD-specific therapy reintroduction.

Effects of CYP3A5 Genotype on Tacrolimus Pharmacokinetics and Graft-versus-Host Disease Incidence in Allogeneic Hematopoietic Stem Cell Transplantation.

Tacrolimus (Tac) is pivotal in preventing acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT). It has been reported that genetic factors, including CYP3A5*3 and CYP3A4*22 polymorphisms, have an impact on Tac metabolism, dose requirement, and response to Tac. There is limited information regarding this topic in alloHSCT. The CYP3A5 genotype and a low Tac trough concentration/dose ratio (Tac C0/D ratio) can be used to identify fast metabolizers and predict the required Tac dose to achieve target concentrations earlier. We examined 62 Caucasian alloHSCT recipients with a fast metabolizer phenotype (C0/dose ratio ≤ 1.5 ng/mL/mg), assessing CYP3A5 genotypes and acute GVHD incidence. Forty-nine patients (79%) were poor metabolizers (2 copies of the variant *3 allele) and 13 (21%) were CYP3A5 expressers (CYP3A5*1/*1 or CYP3A5*1/*3 genotypes). CYP3A5 expressers had lower C0 at 48 h (3.7 vs. 6.2 ng/mL, p = 0.03) and at 7 days (8.6 vs. 11.4 ng/mL, p = 0.04) after Tac initiation, tended to take longer to reach Tac therapeutic range (11.8 vs. 8.9 days, p = 0.16), and had higher incidence of both global (92.3% vs. 38.8%, p < 0.001) and grade II-IV acute GVHD (61.5% vs. 24.5%, p = 0.008). These results support the adoption of preemptive pharmacogenetic testing to better predict individual Tac initial dose, helping to achieve the therapeutic range and reducing the risk of acute GVHD earlier.

Pitahaya (Hylocereus ocamponis)-Peel and -Flesh Flour Obtained from Fruit Co-Products-Assessment of Chemical, Techno-Functional and In Vitro Antioxidant Properties.

The aim of this work was to assess the chemical composition and physico-chemical, techno-functional, and in vitro antioxidant properties of flours obtained from the peel and flesh of pitahaya (Hylocereus ocamponis) to determine their potential for use as ingredients for food enrichment. The chemical composition, including total betalains, mineral content, and polyphenolic profile, was determined. The techno-functional properties (water holding, oil holding, and swelling capacities) were also evaluated. For the antioxidant capacity, four different methodologies, namely ferrous ion-chelating ability assay, ferric-reducing antioxidant power assay; 1,1-Diphenyl-2-picrylhydrazyl radical scavenging ability assay, and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical assay, were used. Pitahaya-peel flour had higher values for protein (6.72 g/100 g), ash (11.63 g/100 g), and dietary fiber 56.56 g/100 g) than pitahaya-flesh flour, with values of 6.06, 3.63, and 8.22 g/100 g for protein, ash, and dietary fiber, respectively. In the same way, pitahaya peel showed a higher content of minerals, betalains, and polyphenolic compounds than pitahaya-flesh flour, with potassium (4.43 g/100 g), catechin (25.85 mg/g), quercetin-3-rhamnoside (11.66 mg/g) and myricetrin (12.10 mg/g) as principal compounds found in the peel. Again, pitahaya-peel flour showed better techno-functional and antioxidant properties than pitahaya-flesh flour. The results obtained suggest that the flours obtained from the peel and pulp of pitahaya (H. ocamponis) constitute a potential material to be utilized as an ingredient in the food industry due to the high content of bioactive compounds such as betalains, phenolic acids, and flavonoids, with notable antioxidant capacity.

Vasoactive intestinal peptide exerts an osteoinductive effect in human mesenchymal stem cells.

Several neuropeptides present in bone tissues, produced by nerve fibers and bone cells, have been reported to play a role in regulating the fine-tuning of osteoblast and osteoclast functions to maintain bone homeostasis. This study aims to characterize the influence of the neuropeptide vasoactive intestinal peptide (VIP) on the differentiation process of human mesenchymal stem cells (MSCs) into osteoblasts and on their anabolic function. We describe the mRNA and protein expression profile of VIP and its receptors in MSCs as they differentiate into osteoblasts, suggesting the presence of an autocrine signaling pathway in these cells. Our findings reveal that VIP enhances the expression of early osteoblast markers in MSCs under osteogenic differentiation and favors both bone matrix formation and proper cytoskeletal reorganization. Finally, our data suggest that VIP could be exerting a direct modulatory role on the osteoblast to osteoclast signaling by downregulating the receptor activator of nuclear factor-κB ligand/osteoprotegerin ratio. These results highlight the potential of VIP as an osteoinductive differentiation factor, emerging as a key molecule in the maintenance of human bone homeostasis.